Theoretical and experimental studies on partitions of γ-substituted butyric acids in chloroform/water and dichloromethane/water systems

Abstract

Having measured the log P value of γ-hydroxybutyric acid (GHB) in chloroform/water and dichloromethane/water systems at T = 25 and 37 °C, the relative log P value for the structural analogue γ-aminobutyric acid (GABA), log P (GABA) - log P (GHB), has been determined theoretically. A combined ab initio/Monte Carlo method for obtaining the internal free energy and the relative solvation free energy, respectively, has been applied for studying the conformational/tautomeric equilibria of GABA in the three solvents. Free energy changes for the partition processes have been calculated within thermodynamic cycles. There is no significant difference in the log P values for the neutral GABA and GHB of -1.22 ± 0.12 at 37 °C, as measured in the chloroform/water system. Using the more polar dichloromethane solvent as the organic phase, the GABA log P increases compared to its log P in chloroform. Because GABA almost entirely takes the zwitterionic form in aqueous solution, it is a key question whether this tautomeric form can partition into a slightly-polar phase. The lack of this ability would be in accord with the experimentally known fact that GABA does not cross the blood-brain barrier. Calculations indicated that the zwitterionic form is more stable than the neutral tautomer by as much as ∼9 kcal/mol in water at 37 °C. Direct partitioning of the zwitterion from the aqueous to the organic phase requires 23 or about 17 kcal/mol increases in free energy to enter the chloroform or dichloromethane phase, respectively. Although partitioning via the neutral form is allowed thermodynamically, equilibrium is reached after the entrance of about 3% of the neutral form into the organic phase. This partition leads to a negligible shift of the neutral form-zwitterion equilibrium in water, leaving essentially all GABA in the aqueous phase.

title = "Theoretical and experimental studies on partitions of γ-substituted butyric acids in chloroform/water and dichloromethane/water systems",

abstract = "Having measured the log P value of γ-hydroxybutyric acid (GHB) in chloroform/water and dichloromethane/water systems at T = 25 and 37 °C, the relative log P value for the structural analogue γ-aminobutyric acid (GABA), log P (GABA) - log P (GHB), has been determined theoretically. A combined ab initio/Monte Carlo method for obtaining the internal free energy and the relative solvation free energy, respectively, has been applied for studying the conformational/tautomeric equilibria of GABA in the three solvents. Free energy changes for the partition processes have been calculated within thermodynamic cycles. There is no significant difference in the log P values for the neutral GABA and GHB of -1.22 ± 0.12 at 37 °C, as measured in the chloroform/water system. Using the more polar dichloromethane solvent as the organic phase, the GABA log P increases compared to its log P in chloroform. Because GABA almost entirely takes the zwitterionic form in aqueous solution, it is a key question whether this tautomeric form can partition into a slightly-polar phase. The lack of this ability would be in accord with the experimentally known fact that GABA does not cross the blood-brain barrier. Calculations indicated that the zwitterionic form is more stable than the neutral tautomer by as much as ∼9 kcal/mol in water at 37 °C. Direct partitioning of the zwitterion from the aqueous to the organic phase requires 23 or about 17 kcal/mol increases in free energy to enter the chloroform or dichloromethane phase, respectively. Although partitioning via the neutral form is allowed thermodynamically, equilibrium is reached after the entrance of about 3% of the neutral form into the organic phase. This partition leads to a negligible shift of the neutral form-zwitterion equilibrium in water, leaving essentially all GABA in the aqueous phase.",

N2 - Having measured the log P value of γ-hydroxybutyric acid (GHB) in chloroform/water and dichloromethane/water systems at T = 25 and 37 °C, the relative log P value for the structural analogue γ-aminobutyric acid (GABA), log P (GABA) - log P (GHB), has been determined theoretically. A combined ab initio/Monte Carlo method for obtaining the internal free energy and the relative solvation free energy, respectively, has been applied for studying the conformational/tautomeric equilibria of GABA in the three solvents. Free energy changes for the partition processes have been calculated within thermodynamic cycles. There is no significant difference in the log P values for the neutral GABA and GHB of -1.22 ± 0.12 at 37 °C, as measured in the chloroform/water system. Using the more polar dichloromethane solvent as the organic phase, the GABA log P increases compared to its log P in chloroform. Because GABA almost entirely takes the zwitterionic form in aqueous solution, it is a key question whether this tautomeric form can partition into a slightly-polar phase. The lack of this ability would be in accord with the experimentally known fact that GABA does not cross the blood-brain barrier. Calculations indicated that the zwitterionic form is more stable than the neutral tautomer by as much as ∼9 kcal/mol in water at 37 °C. Direct partitioning of the zwitterion from the aqueous to the organic phase requires 23 or about 17 kcal/mol increases in free energy to enter the chloroform or dichloromethane phase, respectively. Although partitioning via the neutral form is allowed thermodynamically, equilibrium is reached after the entrance of about 3% of the neutral form into the organic phase. This partition leads to a negligible shift of the neutral form-zwitterion equilibrium in water, leaving essentially all GABA in the aqueous phase.

AB - Having measured the log P value of γ-hydroxybutyric acid (GHB) in chloroform/water and dichloromethane/water systems at T = 25 and 37 °C, the relative log P value for the structural analogue γ-aminobutyric acid (GABA), log P (GABA) - log P (GHB), has been determined theoretically. A combined ab initio/Monte Carlo method for obtaining the internal free energy and the relative solvation free energy, respectively, has been applied for studying the conformational/tautomeric equilibria of GABA in the three solvents. Free energy changes for the partition processes have been calculated within thermodynamic cycles. There is no significant difference in the log P values for the neutral GABA and GHB of -1.22 ± 0.12 at 37 °C, as measured in the chloroform/water system. Using the more polar dichloromethane solvent as the organic phase, the GABA log P increases compared to its log P in chloroform. Because GABA almost entirely takes the zwitterionic form in aqueous solution, it is a key question whether this tautomeric form can partition into a slightly-polar phase. The lack of this ability would be in accord with the experimentally known fact that GABA does not cross the blood-brain barrier. Calculations indicated that the zwitterionic form is more stable than the neutral tautomer by as much as ∼9 kcal/mol in water at 37 °C. Direct partitioning of the zwitterion from the aqueous to the organic phase requires 23 or about 17 kcal/mol increases in free energy to enter the chloroform or dichloromethane phase, respectively. Although partitioning via the neutral form is allowed thermodynamically, equilibrium is reached after the entrance of about 3% of the neutral form into the organic phase. This partition leads to a negligible shift of the neutral form-zwitterion equilibrium in water, leaving essentially all GABA in the aqueous phase.